Immunodeficiency Disorders Overview

Immunodeficiency States

• Immunodeficiency disorders are a diverse group of illnesses arising from abnormalities in the immune system, making individuals susceptible to infections.
• Immune system abnormalities can involve the absence or malfunction of blood cells (lymphocytes, granulocytes, monocytes) or soluble molecules (antibodies, complement components).
• Immune deficiency states are categorized into primary and secondary types.

Primary Immunodeficiency

• Primary immunodeficiencies (PIDs) are disorders resulting from hereditary or intrinsic defects in the immune system.
• PIDs encompass a diverse group of disorders characterized by defects in the development or function of the immune system.
• These defects originate from intrinsic cellular and mediator deficiencies in either innate or adaptive immunity.
• The classification of PIDs is based on the underlying immunological defect.

Innate Immunity Defects

• Defects in phagocytes and the complement system often result in immunodeficiency.
• Phagocytic cell disorders involve inadequacies in the development and/or function of myeloid cells (granulocytes and macrophages).
• Genetically-determined defects of the complement system's functional or regulatory components lead to complement deficiencies.
• Leukocyte defects include both quantitative and qualitative abnormalities.

Quantitative Leukocyte Defects

• Congenital agranulocytosis (Kostmann syndrome) is characterized by a gene defect that hinders G-CSF (granulocyte colony stimulating factor) production, leading to a decline in neutrophil counts and impaired myeloid progenitor cell differentiation.
• Affected patients exhibit features such as pneumonia, otitis media, gingivostomatitis, and perineal abscesses.

Phagocytic Dysfunction

• Primary or intrinsic issues in phagocytes are linked to enzymatic deficiencies within the metabolic pathways essential for microbial killing.
• Chronic granulomatous disease results from NADPH oxidase deficiencies, causing impaired microbial killing within macrophages and neutrophils.
• Myeloperoxidase deficiency, Chediak-Higashi syndrome, and Lazy Leukocyte syndrome also fall under the category of phagocytic dysfunction.

Chronic Granulomatous Disease

• Chronic granulomatous disease (CGD) is an X-linked disorder typically manifesting in the first two years of life.
• CGD arises from mutations affecting gene encoding subunits of NADPH oxidase, which catalyzes the production of reactive oxygen species vital for microbial destruction.
• Patients with CGD exhibit susceptibility to infections stemming from impaired intracellular killing of bacteria and fungi. They commonly experience recurrent infections with catalase-positive bacteria, such as staphylococci.

Specific Enzyme Deficiencies

• Complete deficiency of glucose-6-phosphate dehydrogenase (G6PD) in leukocytes results in a syndrome mimicking chronic granulomatous disease, exhibiting a later onset.
• This condition affects both genders and frequently co-occurs with hemolytic anemia. Meanwhile, myeloperoxidase deficiency results in impaired intracellular killing, leading to candidial and staphylococcal infections.

Chediak-Higashi Syndrome

• Chediak-Higashi syndrome is an autosomal recessive multi-system disorder characterized by recurrent bacterial infections, hepatosplenomegaly, central nervous system abnormalities, and a high incidence of lymphoreticular cancers.
• The primary defect is abnormal intracellular killing due to defective phagosome-lysosome fusion, indicated by abnormal giant granules in white blood cells.
• Patients with this disorder often exhibit albinism, as melanocyte dysfunction prevents pigment transfer to keratinocytes and other epithelial cells.
• The syndrome is also associated with platelet abnormalities that can contribute to bleeding disorders due to platelet dysfunction.

Lazy Leukocyte Syndrome

• Lazy Leukocyte Syndrome affects neutrophil chemotaxis and is linked with neutropenia.
• This condition predisposes individuals to severe bacterial infections.

Complement Deficiency States

• Various complement deficiencies and functional abnormalities lead to increased susceptibility to infections.
• Complement proteins are essential for opsonization, bacterial killing, and chemotaxis.
• Deficiency in early complement components (e.g., C1, C4, C2, or C3) can increase susceptibility to encapsulated organisms (such as Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae).
• Deficiencies in late complement components (e.g., C5-C9) impair the formation of the membrane attack complex (MAC).

Defects in Lymphocyte Maturation

• Antibody deficiencies reflect impaired B cell function due to abnormalities in intrinsic B cells or defects in T cells that affect B cell activation and maturation.
• Combined immunodeficiencies are characterized by impaired development and/or function of T lymphocytes and abnormal B cell function.

Defects in B Cell Function

• Defective antibody responses can result from issues like X-linked agammaglobulinemia (lack of B cell maturation) or hyper-IgM syndrome (impaired class switching).
• Such deficiencies lead to recurrent pyogenic infections, particularly affecting upper and lower respiratory tract and ear (otitis media).
• A variety of diseases linked to B-cell function exist, spanning from complete absence of B cells to selective deficits in specific immunoglobulin classes.

X-linked (Bruton) Agammaglobulinemia

• X-linked agammaglobulinemia is a disorder localized to the long arm of the X chromosome.
• The condition primarily impacts young boys, leading to a virtual absence of circulating B cells, resulting in severely low levels of all immunoglobulin subclasses (IgG, IgM, IgA, IgD, IgE).
• Affected individuals display a lack of antibody production, pre-B cells in the bone marrow, and defective immunoglobulin production caused by a lack of a tyrosine kinase.

Secondary (Acquired) Immunodeficiencies

• Major causes of secondary immunodeficiencies include malnutrition, viral infections (e.g., HIV), cancer metastases/leukemias (affecting bone marrow), cancer therapies (chemotherapy/irradiation), corticosteroids (immunosuppressants), and chronic diseases (e.g., diabetes).

Malnutrition

• Malnutrition, globally, is a significant cause of immunodeficiency.
• Deficiencies in calories, essential macronutrients, or micronutrients severely impair immune responses.
• Severely undernourished individuals have an increased risk of infection.

Immunodeficiency Secondary to Drug Therapies

• Immunomodulatory drugs can severely suppress immune functions.
• Drugs like cyclophosphamide, azathioprine, and mycophenolate mofetil directly affect DNA or its synthesis.
• Steroids induce lymphocytopenia, monocytopenia, and neutrophilia and hinder cytokine synthesis and T-cell activation and proliferation.

Human Immunodeficiency Virus (HIV)

• HIV infection is a major cause of immunodeficiency worldwide, second only to malnutrition.
• HIV primarily affects CD4+ T cells and macrophages.

HIV Infection Pathologic Effects

• HIV pathologic effects are directly linked to interaction with CD4 receptors on T cells and cells expressing the CD4 receptor (macrophages, monocytes, microglial cells).
• Some HIV strains, termed macrophage-tropic, require CCR5 receptors on cell surfaces to cause infection. Other strains require CXCR4 for binding and cellular uptake.